A major goal of cancer therapy is preferential destruction of malignant cells, with sparing of normal tissues; the challenge is to maximize the selectivity of the therapy. The technique of photochemotherapy permits double selectivity, since damage requires the simultaneous presence of a photosensitizer (PS) and light. The amount of selectivity depends on both the degree of preferential accumulation of the PS in the targeted cells and the extent of the spatial localization of illumination to the target. Most currently employed PS such as hematoporphyrin derivative (HPD) do not have high levels of preferential accumulation in their target cells. In contrast, the preferential accumulation of cationic photosensitizing dyes by carcinoma cell mitochondria permits very selective lightinduced killing of malignant cells in vitro and in vivo. This approach of "selective carcinoma cell photolysis" (SCCP) shows much higher selectivity for carcinomas than any other technique for photochemotherapy. Our long range goal is to develop SCCP into an effective therapy, by optimizing the photosensitizers (PS), defining the damage processes and maximizing in vivo efficacy in animal models. We will synthesize new cationic, carcinomaselective photosensitizers seeking compounds absorbing at long wavelengths which can sensitize oxygenated and hypoxic cells. SCCP will be studied in vitro using human and murine carcinoma cell lines and isolated mitochondria, examining damage site(s) and mechanism(s) of phototoxicity. The technique will be evaluated, characterized and optimized in vivo, using subcutaneous human and murine carcinomas and laser radiation administered through fiber optics. Synergistic effects of infrared laser-induced hyperthermia, glycolysis inhibitors, electrophilic compounds and the combined use of cationic and anionic PS will be explored. SCCP can be used for any lesions accessible to light transmitted through the body surface or internally, via an optical fiber. The high specificity of lightinduced damage permits killing of tumor cells with sparing of overlying and adjacent normal tissues. Thus, cutaneous, endobronchial, intraabdominal, bladder and central nervous system malignancies may be amenable to SCCP.